Novel means first to better characterize and then to treat infection with major respiratory pathogens using existing or newly developed strategies are a primary focus of this important project within the Clinical Research Section. Beginning with the emergence of the pandemic strain of A(H1N1)pdm09 influenza in April 2009, our section undertook clinical research efforts to help better characterize and treat infection with both novel and seasonal subtypes of influenza. An initial treatment trial involving open-label administration of two units of hyperimmune plasma to 98 hospitalized patients with severe influenza suggested that investigational arm participants might have fewer days in the hospital, in the ICU, on mechanical ventilation, and may have improved disposition at Day 7. Based upon these highly suggestive trends, the CRS then launched a follow-up multicenter trial (called IRC005) enrolling patients with severe influenza A infection who were randomized in a double-blind manner to receive either high-titer (hyperimmune) plasma or a low-titer (control) plasma in addition to standard-of-care treatments. 140 subjects out of a desired goal of 150 were randomized in this trial, with the primary endpoint being an assessment of clinical status using an ordinal outcome score as measured at Day 7. The major finding of IRC005 was that the use of high-titer immune plasma did not confer a clinical benefit over non-immune plasma in patients hospitalized with influenza A, and thus this immunotherapy could not be recommended as a useful adjunctive treatment strategy for future patients. As a separate trial launched through the INSIGHT clinical trials network, we also conducted an international multi-center randomized, double-blind, placebo-controlled study of hyperimmune intravenous immunoglobulin (IVIG) versus standard-of-care in hospitalized patients with severe influenza A or B. This clinical outcome trial was preceded by successful completion of a multi-center pilot trial in 31 patients through domestic US sites within the INSIGHT network that showed that administration of IVIG to hospitalized patients or outpatients was safe, significantly boosted HAI titers against the infecting influenza A subtypes, and could be conducted at clinical sites while maintaining the blind. By June, 2018, the trial reached and actually exceeded the accrual goal of the desired number (320) needed to power the endpoint of clinical improvement at Day 7 of illness. Similar to IRC005, however, no treatment benefit was found for IVIG in patients with influenza A. Surprisingly, a significant treatment benefit was found for patients hospitalized with influenza B infection despite the lower antibody titers present in IVIG against influenza B virus. We have also completed two randomized international multicenter trials evaluating 1) the virologic and clinical correlation of triple combination anti-influenza treatment versus monotherapy in at-risk populations (IRC003), and 2) the use of virologic assessments in measuring the effects of oseltamivir versus placebo in mild outpatient disease (IRC004). In IRC003, 80 of 200 (40.0%) participants in the combination arm had detectable viral shedding at Day 3 compared to 97 of 194 (50.0%) (95%C.I. 0.2-19.8%, p=0.046) in the control arm. Despite this effect on viral shedding, however, there was no observed benefit in multiple clinical endpoints. Further investigations are needed to understand the lack of clinical benefit when a difference in virologic outcome is identified. In addition to the ongoing interventional trials mentioned above, we continue to contribute to the management and oversight of two large international observational protocols for outpatients or hospitalized patients with seasonal influenza infection, as well as a third protocol looking at the genomic host response, all administered under the auspices of the INSIGHT network. In the realm of ongoing biodefense-related initiatives, we continue to 1) monitor yearly the clinical and psychological status of a subset of patients previously exposed to anthrax as a result of the October 2001 anthrax attacks, and 2) continue to enroll patients on a protocol designed to permit diagnosis and characterization of patients presenting with unusual, previously undiagnosed infectious or inflammatory conditions. The Special Clinical Studies Unit (SCSU) with the NIH Clinical Center was one of three special high containment patient care units within the US originally called upon to hospitalize and provide care to medically-evacuated HCWs exposed to or infected with Ebola virus in 2014-15. The section continues to provide the medical oversight to the SCSU in the event that patients or staff suffering high-risk exposures to select agents require observation and/or care under conditions of high containment. We have also aligned ourselves closely with the Special Pathogens Research Network of 10 domestic U.S. medical centers capable of caring for Ebola-infected patients in the event of medical evacuations from overseas. The section helped design and orchestrate the only multicenter randomized controlled safety and efficacy study (PREVAIL II) of putative MCMs in the treatment of patients with confirmed Ebola infection during the recent West African crisis. The first investigational countermeasure studied was a triple monoclonal antibody product ZMapp. Although the goal was to enroll a total of 200 patients, the trial was terminated in early January 2016 due to the extinction of new cases of Ebola in the affected countries. By that time a total of 71 evaluable patients had been enrolled at sites in Liberia, Sierra Leone, Guinea, and the United States. While the observed posterior probability that ZMappTM plus oSOC was superior to oSOC alone reached 91.2%, this fell short of the predefined threshold of 97.5% required to establish efficacy. However, these data suggest at least the possibility of a potential beneficial effect of ZMapp had it been possible to complete full accrual. In concert with WRAIR, we successfully completed a phase 1 randomized, double-blind dose-escalating safety and immunogenicity trial of (VSVG-ZEBOV) vaccine in a prime-boost strategy in late 2014 and early 2015. This study established the safety parameters of the experimental vaccine as well as provided comparative immunogenicity data on the three different dosing levels tested. In Fall 2016 NIAID also launched an ongoing pre-exposure vaccination protocol called PREPARE utilizing VSVG-ZEBOV vaccine to immunize HCWs, BSL-4 Laboratory staff, and other at-risk personnel against Ebola virus infection. The protocol features randomization to a homologous booster immunization at month 18 to determine whether the booster further augments antibody levels induced by the primary immunization. Current enrollment as of early August 2019 now exceeds 160 participants. Finally, with the emergence of the 10th outbreak of Ebola virus infection in the Democratic Republic of the Congo (DRC) in August 2018 that has now grown to be the second largest recorded outbreak in history, NIAID collaborated with the Institut National pour la Recherche Biomedicale (INRB), the WHO, and several international partners to design and implement a randomized controlled trial (RCT) of 4 different promising investigational countermeasures against Ebola in that country. As of early August, 2019, the RCT has been open at 4 different Ebola treatment centers and is rapidly approaching its accrual goal of 725 patients. Results of this RCT should help determine which countermeasure(s) provide the best treatment against this highly lethal infection.